Alzheimer's disease (AD) and Parkinson's disease (PD) are the most frequent progressive neurodegenerative diseases affecting millions of people in the world. Because a significant percentage of patients share common clinical and pathological features from both entities, this seems to indicate the existence of a common pathological mechanism. Based on in vitro and in situ data, an unified molecular oxidative stress model induced by dopamine (DA), 6-hydroxydopamine (6-OHDA); 5,6 & 5,7-dihydrytryptamine (5,6 & 5,7 MT); amyloid beta 25-35 (Aβ25-35), and metals [e.g. iron (Fe2+), copper (Cu2+), zinc (Zn2+), manganese (Mn2+)] has been widely proposed as a possible explanation of neural loss in AD/PD overlapping cases. This hypothesis might contribute to a better understanding of the pathophysiology cascades of both disorders, and also support the notion that oxidative stress generated by H2O2 represent an essential molecule of intracellular signalization leading to cell death.
Therefore, an interesting approach for developing new pharmaceutical compounds for treating neurodegenerative diseases may be designing compounds which inhibit cellular oxidative stress. Reactive oxygen species (ROS), such as oxygen radical superoxide (O2) or hydrogen peroxide (H2O2), are produced during normal metabolic processes and perform several useful functions (Reactive oxygen species and the central nervous system, Halliwell B., J Neurochem.; 1992, 59 859: 1609-1623). Cells are provided with several mechanisms to control levels of these oxidative agents, for instance, superoxide dismutase (SOD), glutathione or vitamin E. In normal physiological conditions, a balance between ROS and these anti-oxidative mechanisms exists. An excessive production of ROS and a loss of efficiency of the anti-oxidative defences can lead to pathological conditions in cells and provoke tissue damage. This event seems to occur more dramatically in neurons, because of their high rate of metabolic activity, and thus seems to be related to a series of degenerative processes, diseases and syndromes, for example, Alzheimer's Disease, Parkinson's Disease, amyotrophic lateral sclerosis (ALS) and schizophrenia (Glutathione, oxidative stress and neurodegeneration, Schulz et al., Eur. J. Biochem.; 2000, 267. 4904-4911). Also other diseases or pathological conditions have been related to oxidative stress, such as Huntington's Disease (Oxidative damage in Himtington's disease, Segovia J. and Perez-Severiano F, Methods Mol. Biol; 2004; 207: 321-334), brain injuries, such as stroke and ischemia, (Oxidative Stress in the Context of Acute Cerebrovascular Stroke, El Kossi et al., Stroke; 2000; 31: 1889-1892), diabetes (Oxidative stress as a therapeutic target in diabetes: revisiting the controversy, Wiernsperger N F, Diabetes Metab.; 2003; 29, 579-85), multiple sclerosis (The role of oxidative stress in the pathogenesis of multiple sclerosis: the need for effective antioxidant therapy, Gilgun-Sherki Y. et al., J. Neurol: 2004; 251 (3): 261-8), epilepsy (Oxidative injury in epilepsy: potential for antioxidant therapy?, Costello D. J. and Delanty N., Expert. Rev. Neurother.; 2004; 4(3): 541-553), atherosclerosis (The oxidative stress hypothesis of atherogenesis, Iuliano L., Lipids; 2001; 36 suppl: S41-44), Friedreich's Ataxia (Oxidative stress mitochondrial dysfuntion and cellular stress response in Friedreich's ataxia, Calabrese et al., J. Neurol. Sci.; 2005) and heart failure (Oxygen, oxidative stress, hypoxia and heart failure, Giordano F. J., J. Clinic. Invest.; 2005; 115 (3): 500-508). Treatments that lead to an enhancement of the anti-oxidative mechanisms may slow the progression of some of the mentioned diseases.
Collismycins are 2,2′-bypiridine molecules which have been isolated from Streptomyces species. Several kinds of these molecules were firstly isolated by Gomi et al. (Novel Antibiotics SF2738A, B and C and their analogues produced by Streptomyces sp., Gomi et al., J. Antibiot., 1994, 47:1385-1394) from a culture of Streptomyces sp. SF2738, and their structure was described by spectral analyses and chemical conversion. Biological activities of different types of collismycins were also studied and, among them, specially Collismycin A was described to be endowed with antibiotic activity against some bacteria and a wide range of fungi. This antifungal activity against some species, such as, Saccharomyces cerevisiae and Candida albicans, has been demonstrated by Stadler et al. (Antifungal Actinomycete Metabolites Discovered in a Differential Cell-Based Screening Using a Recombinant TOPO1 Deletion Mutant Strain, Stadler et al., Arch. Pharm. Med. Chem., 2001, 334: 143-147). Two yeast strains, a wild type (ScAL 141) and a recombinant topoisomerase 1 (TOPO1) deletion mutant (ScAL 143), were used for the screening of compounds produced by actinomycetes strains WS 1410 and BS 1465. They were also used to test the biological activities of collismycins, among other compounds, with the activity of camptothecin as a reference. Results show that the mechanism of action of collismycins is not based on the inhibition of topoisomerase 1, because collismycins are active against both wild type and mutant yeast strains.
Cytotoxicity is another biological activity that has been described for some collismycins. This property was also demonstrated by Gomi et al. (see above) in a study of the cytotoxic ability of these molecules on P388 murine leukaemia cells. In JP5078322 Collismycin is related to the use of Collismycins A and B as antitumoral substances, useful as carcinostatic agents, for parenteral or oral administration. A lot of other patent publications refer to the use of Collismycins A and B in combination with other antitumoral agents. This is the case, for example, of WO02/053138, which discloses the use of incensole and/or furanogermacrens, derivatives, metabolites and precursors thereof in the treatment of neoplasia, particularly resistant neoplasia and immune dysregulatory disorders. These compounds may be administered alone or in combination with conventional chemotherapeutic, anti-viral, anti-parasite agents, radiation and/or surgery. The listed chemotherapeutic agents include Collismycins A and B.
Another biological activity of collismycins was described by Shindo et al. in 1994 (Collismycins A and B. novel non-steroidal inhibitors of dexamethasone-glucocorticoid receptor binding, Shindo et al., J. Antibiot., 1994, 47: 1072-1074). It was suggested that Collismycin A and its isomer B could have an anti-inflammatory activity inhibiting the dexamethasone-glucocorticoid receptor binding, although no complementary results to this study seem to have been published.
A synthesis of Collismycin A has been described by Trecourt et al. in 1998 (First Synthesis of Cacrulomycin E and Collismycins A and C. A New Synthesis of Caerulomycin A, Trecourt et al. J. Org. Chem., 1998, 63:2892-2897) starting from 2,2-bipyridine N-oxide. Functionalization at C-4 and C-6 through different pathways leads to 6-bromo-4-methoxy-2,2′-bipyridines; a subsequent metalation reaction introduces a methylthio moiety at C-5. In a last step of the synthesis pathway, Br at C-6 is substituted by a formyl group which reacts with hydroxylamine to provide Collismycin A. This document is herewith incorporated by reference into the present application.
In particular, Collismycin A presents the following structure:
and Collismycin B:

Some other 2,2′-bipyridine compounds with structures close to that of Collismycin have been described in the literature.
Some examples are: Pyrisulfoxin-A (N. Tsuge et al., J. Antibiot. 52 (1999) 505-7)
Caerulomycin-B; Cerulomycin-B
Caerulomycin-C; Cerulomycin-C
Caerulomycin; Caerulomycin-A; Cerulomycin
